Assessment of raloxifene, estradiol-17β, dl-ormeloxifene and levormeloxifene on thrombin activity
-
William R. Surin
,
Hiralal Bhalla
Abstract
Background: Cancer is one of the leading causes of morbidity and mortality globally. Cancer-associated thrombosis is well established in clinical settings, and thrombin has been found to induce angiogenesis at cancer sites. This establishes a link between cardiovascular diseases and cancer, where cancer and thrombin have been intricately associated. Various selective estrogen receptor modulators (SERMs) have been reported to exhibit anticancer activity. Therefore, we investigated estradiol-17β and SERMs dl-ormeloxifene (centchroman), raloxifene and levormeloxifene (l-centchroman) for their anticancer effects and their effect on thrombin activity.
Methods: Anticancer activity was assessed against PC-3 cell line by flow cytometry following treatment with estradiol-17β and SERMs at 10 nM–1 mM concentrations. The cells were stained with propidium iodide and the percentage of cells in the sub-G0/G1 region was considered apoptotic. Thrombin inhibitory effect was evaluated by thrombin inhibition assay in vitro following incubation with 100 nM–3 mM concentrations of estradiol-17β or various SERMs. Further, the effect of estradiol-17β and SERMs on endogenous thrombin generation potential (ETP) was assessed by thrombin generation assay on rat plasma in vitro.
Results: These compounds exhibited >90% cell death in PC-3 cell lines at 1 mM concentration except estradiol-17β. Neither estradiol-17β, dl-ormeloxifene and levormeloxifene showed any thrombin inhibitory or enhancing activity in thrombin inhibition assay, nor did they show any effect on ETP on rat plasma in vitro. However, raloxifene inhibited thrombin activity in a concentration-dependent manner. Raloxifene decreased ETP of the plasma at 3 and 1 mM,which is equivalent to that of 30–100 U/mL of heparin. Interestingly, raloxifene increased thrombin generation at lower concentrations and it inhibited thrombin generation at higher concentrations.
Conclusions: These observations suggest that dl-ormeloxifene, estradiol-17β and levormeloxifene do not possess thrombin inhibitory activity. Raloxifene possesses thrombin modulatory effect in addition to its anticancer activity, and this observation may help us in understanding the thromboembolic complications associated with raloxifene.
Acknowledgments
The authors wish to thank the Central Animal Facility, Indian Institute of Science (IISc), Bangalore, for providing the animals for the study, and Prof P. Kondaiah, Molecular Reproduction, Development and Genetics, IISc, for generously providing PC-3 cell lines for the study. We acknowledge the use of a plate reader, SpectraMax M5e (Molecular Devices), purchased through a DST grant to Prof. A. G. Samuelson. This study was partially supported by a CPDA grant to W.R.S.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
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©2014 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorial
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- Review
- Review on treatment of premenstrual syndrome: from conventional to alternative approach
- Genotoxicity and Cytotoxicity
- Sodium valproate, a histone deacetylase inhibitor ameliorates cyclophosphamide-induced genotoxicity and cytotoxicity in the colon of mice
- Vascular Conditions
- PKC-δ isozyme gene silencing restores vascular function in diabetic rats
- Association of diet and anthropometric measures as cardiovascular modifiable risk factors in young adults
- Assessment of raloxifene, estradiol-17β, dl-ormeloxifene and levormeloxifene on thrombin activity
- Inflammation
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- Infection
- Antinociceptive and antiedematogenic effect of pecan (Carya illinoensis) nut shell extract in mice: a possible beneficial use for a by-product of the nut industry
- Phytotherapy
- Toxicological evaluation of the lyophilized fruit juice extract of Annona muricata Linn. (Annonaceae) in rodents
- Analgesic, anti-inflammatory and antipyretic effects of Ixora coccinea
- Antidepressant, anxiolytic, and anticataleptic effects of aqueous leaf extract of Antiaris toxicaria Lesch. (Moraceae) in mice: possible mechanisms of actions
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Articles in the same Issue
- Frontmatter
- Editorial
- Get more of the Journal of Basic and Clinical Physiology and Pharmacology
- Review
- Review on treatment of premenstrual syndrome: from conventional to alternative approach
- Genotoxicity and Cytotoxicity
- Sodium valproate, a histone deacetylase inhibitor ameliorates cyclophosphamide-induced genotoxicity and cytotoxicity in the colon of mice
- Vascular Conditions
- PKC-δ isozyme gene silencing restores vascular function in diabetic rats
- Association of diet and anthropometric measures as cardiovascular modifiable risk factors in young adults
- Assessment of raloxifene, estradiol-17β, dl-ormeloxifene and levormeloxifene on thrombin activity
- Inflammation
- Antibacterial activity of the body wall extracts of sea cucumber (Invertebrata; Echinodermata) on infectious oral streptococci
- Chronic ethanol use in alcoholic beverages by HIV-infected patients affects the therapeutic window of stavudine, lamivudine and nevirapine during the 9-month follow-up period: using chronic alcohol-use biomarkers
- Preclinical efficacy of melatonin in the amelioration of tenofovir nephrotoxicity by the attenuation of oxidative stress, nitrosative stress and inflammation in rats
- Infection
- Antinociceptive and antiedematogenic effect of pecan (Carya illinoensis) nut shell extract in mice: a possible beneficial use for a by-product of the nut industry
- Phytotherapy
- Toxicological evaluation of the lyophilized fruit juice extract of Annona muricata Linn. (Annonaceae) in rodents
- Analgesic, anti-inflammatory and antipyretic effects of Ixora coccinea
- Antidepressant, anxiolytic, and anticataleptic effects of aqueous leaf extract of Antiaris toxicaria Lesch. (Moraceae) in mice: possible mechanisms of actions
- Pharmacological evaluation of the analgesic and anxiolytic activities of Jobelyn® in mice
- Abortifacient potential of ethanolic seed extract of Caesalpinia bonducella in female albino rats
